Specific delivery of chemotherapeutic agents to desired target sites with a minimum of systemic side effects constitutes one of the ongoing challenges of chemotherapy. Drugs administered parenterally have activity in areas of the body where activity is not desired. In 1974, Kramer proposed albumin microspheres as vehicles for achieving specificity in drug delivery. J. Pharm. Sci., 63, 1646-1647 (Oct. 1974). Entrapment of the anti-cancer drug mercaptopurine was demonstrated but not specificity of delivery. Local compartmentalization of water soluble chemotherapeutic agents at desired target sites, if it could be achieved, would permit administration of much lower doses by largely eliminating systemic dilution of the drug. In addition, many of the adverse side effects that are often the result of systemic distribution could be eliminated. Unfortunately, prior to the present invention, no system of administration has been provided which can effectively deliver therapeutic agents intravascularly to a selected site.
Freeman et al proposed in 1960 that magnetic iron particles might be used as a means for transporting radiation or some healing chemical to a particular spot in the body, the particles being magnetically directed. J. App. Phys., Supp. Vol. 31, 404S-405S (May 1960). It was suggested that the iron particles could be alloyed with the proper choice of radioactive element, or that they could be coated with an adsorbed layer of a therapeutic agent. Meyers et al also suggested the use of carbonyl iron particles as vehicles for site specific delivery of chemotherapeutic agents. Amer. J. Roentg., 90, 1068-1077 (Nov. 1963). Magnetic iron particles of 1 to 3 microns in diameter were shown to be temporarily localized in the vessels or gastrointestinal tract of dogs with a magnetic field of approximately 5,000 gauss. The particles were removed by blood flow when the magnet was removed. However, it appeared that a few of the particles had been pulled through the artery into the tissues by the magnetic field, and remained there after removal of the magnetic field.
U.S. Pat. No. 3,474,779, granted Oct. 28, 1969, describes a method for administering therapeutic agents in which magnetic microspheres of a size up to 5 microns are intravascularly administered so that they pass into a capillary bed where they are caught by an applied magnetic field, and magnetically retained in the capillary bed until the therapeutic agent contained in the microspheres is released. It is proposed that this method can be used for administering anti-cancer drugs. No specific examples are given, and there is no suggestion that the microspheres would remain in the capillary bed after removal of the magnetic field.
It is known that the surface properties of magnetic particles, such as carbonyl iron, lead to irreversible intravascular clumping upon exposure to a magnetic field unless they are coated with electronegative polymer such as albumin. See Nakamura et al, J. App. Phys., 42, 1320-1324 (1971); Alksne et al, Surgery, 60, 212 (1966); and Mosso et al, Ann. Surg., 178:5, 633 (1973).
Takai et al proposed that magnetic materials coated with organic polymers could be used as carriers for drugs and x-ray contrast media, and that they could be localized in a desired area of the body by means of permanent magnet. Such a coated magnetic material was orally administered to a patient with peptic ulcers and localized on the lesions, which permitted sharper x-ray photos of the ulcers to be obtained. Chemical Abstracts, Vol. 80, No. 5, page 293, Abstract 52392a (1974).
Microcapsules containing magnetic particles are disclosed in U.S. Pat. No. 2,971,916. Microcapsules of 3 to 150 microns in diameter are formed by coacervation, the capsules having walls of hardened organic colloid material enclosing an oily liquid containing a dispersion of magnetic powder. No medical application is suggested, the capsules being indicated as useful for imprinting of data on record sheets.
U.S. Pat. No. 3,663,687, issued May 16, 1972, proposes the use of biodegradable microspheres for the intravascular administration of therapeutic agents. The microspheres are dimensioned so that they will lodge in the capillaries. The microspheres are dissolved by enzymatic action, thereby releasing the therapeutic agent. The examples disclose microspheres having sizes ranging from 10 to 50 microns. This patent further discloses that the rate of release of the therapeutic agent can be controlled by cross-linking of the protein material forming the microspheres, by either heat or chemical treatment.
U.S. Pat. No. 3,937,668, issued Feb. 10, 1976, describes a method for preparing albumin microspheres which can be used for delivery of therapeutic agents, among other uses. It is stated that the microspheres may range in size from 1 to 200 microns.